1. The Role of Sphingosine-1-Phosphate Transporter Spns2 in Immune System Function.
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Nijnik, Anastasia, Clare, Simon, Hale, Christine, Jing Chen, Raisen, Claire, Mottram, Lynda, Lucas, Mark, Estabel, Jeanne, Ryder, Edward, Adissu, Hibret, Adams, Niels C., Ramirez-Solis, Ramiro, White, Jacqueline K., Steel, Karen P., Dougan, Gordon, and Hancock, Robert E. W.
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SPHINGOSINE-1-phosphate , *IMMUNE system , *LIPIDS , *EMBRYOLOGY , *CELL membranes , *ATP-binding cassette transporters , *IMMUNOSUPPRESSIVE agents - Abstract
Sphingosine-l-phosphate (SIP) is lipid messenger involved in the regulation of embryonic development, immune system functions, and many other physiological processes. However, the mechanisms of SIP transport across cellular membranes remain poorly understood, with several ATP-binding cassette family members and the spinster 2 (Spns2) member of the major facilitator superfamily known to mediate SIP transport in cell culture. Spns2 was also shown to control SIP activities in zebrafish in vivo and to play a critical role in zebrafish cardiovascular development. However, the in vivo roles of Spns2 in mammals and its involvement in the different SIP-dependent physiological processes have not been investigated. In this study, we characterized Spns2-null mouse line carrying the Spns2tmlalKOMP)Wtsi allele (Spns2tmla). The Spns2tmla/tmla animals were viable, indicating a divergence in Spns2 function from its zebrafish ortholog. However, the immunological phenotype of the Spns2tmla/tmla mice closely mimicked the phenotypes of partial SIP deficiency and impaired SIP-dependent lymphocyte trafficking, with a depletion of lymphocytes in circulation, an increase in mature single-positive T cells in the thymus, and a selective reduction in mature B cells in the spleen and bone marrow. Spns2 activity in the nonhematopoietic cells was critical for normal lymphocyte development and localization. Overall, Spns2tmla/tmla resulted in impaired humoral immune responses to immunization. This study thus demonstrated a physiological role for Spns2 in mammalian immune system functions but not in cardiovascular development. Other components of the SIP signaling network are investigated as drug targets for immunosuppressive therapy, but the selective action of Spns2 may present an advantage in this regard. [ABSTRACT FROM AUTHOR]
- Published
- 2012
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